Method and composition for the treatment of epidermal irritations and infections

ABSTRACT

A stannous fluoride composition is disclosed. The composition comprises stannous fluoride and at least one zinc containing compound. The zinc containing compounds stabilize and prevent hydrolysis of the stannous ions resulting in a stannous fluoride composition for use in the treatment of epidermal irritations and infections.

This application is A 371 OF PCT/US99/13048 Jun. 9, 1999 which claimsbenefit of Ser. No. 60/088,560 Jun. 9, 1998.

FIELD OF THE INVENTION

The present invention relates to an improved stannous fluoridecomposition for the treatment of epidermal irritations and infections.

BACKGROUND OF THE INVENTION

Stannous fluoride has been used in dentistry since the 1950's to preventdental cavities. Norman Tinanoff outlines 40 years of human and animalstudies with some studies having greater efficacy than others in “Reviewof the Antimicrobial Action of Stannous Fluoride” (The Journal ofClinical Dentistry Vol. II 1990). U.S. Pat. No. 4,097,590 “Methods andCompositions for Treatment of Bacteria and Fungus infections of theskin” discloses treatment for vulgaris and athletes foot with a solublefluoride salt. The present inventor previously determined that stannousfluoride can be used for treating diseases having viral etiology. (U.S.Pat. No. 5,098,716 to Embro).

Both the shelf life and antimicrobial effect of a stannous fluorideproduct depend on stability of the active stannous ion (Sn+2). Productsformulated for home use achieve stability of the stannous ion by addingglycerin or other water-insoluble materials to reduce hydrolysis andoxidation. Aqueous formulations employed chelating agents which bindstannous fluoride and create a stannous reservoir that acts both as asupply of stannous ions and an antioxidant. Majeti et. al. (U.S. Pat.No. 5,004,597), developed a dentifrice stabilization system for stannousfluoride by utilizing stannous chloride as an antioxidant with stannousreservoir and sodium gluconate as a chelating agent to protect stannousfluoride from hydrolysis. Other chemicals used in stannous fluoridestabilization include polyvinyl alcohol (PVA), tripolyphosphates,copolymers of vinyl-methylether and maleic anhydride. However, the useof these and other complexing agents for stannous fluoride stabilizationcan limit the bioavailability of stannous ions for a therapeutic effect.

In view of the foregoing, there is a need to provide improved stannousfluoride compositions.

SUMMARY OF THE INVENTION

The present invention relates to an improved stannous fluoridecomposition comprising stannous fluoride and at least one zinccontaining compound. The inventor has shown that the improvedcomposition is more stable and less toxic than a stannous fluoridecomposition that does not contain a zinc compound. The inventor has alsoshown that the improved composition of the invention allows one todecrease the dose of stannous fluoride required to achieve a therapeuticeffect.

The inventor has demonstrated that the improved composition of theinvention is effective in treating epidermal irritations and infectionsand their symptoms. Accordingly, the present invention also provides amethod of treating an epidermal irritation or infection comprisingadministering an effective amount of a composition comprising stannousfluoride and at least one zinc containing compound to an animal in needthereof.

Other features and advantages of the present invention will becomeapparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples while indicating preferred embodiments of the invention aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF THE INVENTION COMPOSITIONS OF THE INVENTION

The present invention relates to an improved stannous fluoridecomposition comprising stannous fluoride and at least one zinccontaining compound. This composition may be referred to herein as “thecomposition of the invention”.

The composition of the invention is markedly improved over a compositioncontaining stannous fluoride without any zinc compounds in severalrespects. Firstly, stannous fluoride undergoes hydrolysis and oxidationin aqueous environments which results in the loss of stannousbioavailability due to the precipitation of stannous hydroxide. The zinccontaining compounds stabilize the stannous fluoride by preventing theoxidation and hydrolysis of the stannous ion. Zinc ions have a greateraffinity than stannous ions for hydroxides and other anions in aqueoussolutions. As a result the zinc in the composition of the invention willcomplex the hydroxides and inhibit hydrolysis and precipitation of thestannous ions. In particular, the inventor has demonstrated that astannous fluoride solution containing zinc gluconate remained stable,without precipitation, for at least 3 months. In contrast, a stannousfluoride solution without zinc gluconate extensively precipitated.Secondly, the zinc compounds buffer the hydrogen ion which promotes anelevated pH. This makes the composition more suitable for topical use asmore acidic formulations can irritate or cause a burning sensation ofthe skin. Thirdly, the present inventor has unexpectedly found that thezinc compounds act synergistically with and potentiate the activity ofthe stannous fluoride. In particular, the present inventor hasdemonstrated that in the composition of the invention the stannousfluoride works better than when twice the dose is used in a compositionthat does not contain the zinc compounds. Consequently, the dose of thestannous fluoride can be significantly lowered in the composition of theinvention resulting in a less toxic composition.

As mentioned above, inclusion of zinc compounds in the composition ofthe present invention stabilizes and enhances the efficacy of thestannous fluoride. Using zinc containing compounds in the compositionalso has additional advantages in that zinc is widely recognized ashaving medicinal and healing properties. In particular, 1) zinc isessential for life; 2) zinc is necessary for over 100 enzymes (i.e.,alcohol dehydrogenase carboxypeptidase); 3) zinc maintains body levelsof Vitamin A; 4) zinc is important in sex organ function andreproduction; 5) zinc is important for DNA/RNA synthesis; 6) zinc canimprove cell-mediated immunity; and 7) zinc is incorporated in hundredsof dermatological formulas to help maintain healthy skin cells. Usingstannous compounds with the stannous fluoride will not provide the addedbenefits that zinc does as stannous is not essential for life and is notnecessary for enzyme function.

The zinc containing compound can be any compound containing zincincluding zinc carboxylates and zinc salts. The zinc carboxylate ispreferably selected from one or more of zinc gluconate, zinc tartrate,zinc malate, zinc propionate, zinc citrate and zinc acetate. Morepreferably, the zinc carboxylate is zinc gluconate. The zinc salt ispreferably selected from zinc chloride, zinc sulfate, zinc phosphate,zinc pyrophosphate, zinc oxide or zinc thiocynate. Preferably, the zincsalt is zinc chloride.

The composition of the invention preferably comprises stannous fluoridein a concentration ranging from about 0.01 wt % to about 10.0 wt % andone or more zinc containing compound in an amount from about 0.05 wt %to about 20.0 wt %.

In a preferred embodiment, the composition comprises stannous fluorideand zinc gluconate. The inventor has shown that a composition comprisingstannous fluoride and zinc gluconate provides significantly greaterefficacy in the treatment of a viral, bacterial and fungal infections ascompared to a stannous fluoride composition alone. In particular, theinventor has demonstrated that with the improved composition one can useone half the amount of stannous fluoride as is used in a compositioncontaining stannous fluoride alone with improved results.

Preferably, the stannous fluoride is provided in a concentration rangingfrom about 0.1 wt. % to about 8.0 wt. % and zinc gluconate is providedin concentration ranging from about 0.5 wt. % to about 10.0 wt. %. Mostpreferably, the composition comprises 0.20 % stannous fluoride and 1.5%zinc gluconate, in a non-aqueous medium such as glycerin.

The composition may additionally contain zinc chloride in aconcentration ranging from about 0.5 wt. % to about 5.0 wt. %. Theaddition of zinc chloride may be useful in compositions with a highaqueous content (i.e. >80% water).

The composition of the invention can include more than one zinccontaining compound. For example, the zinc compound may be zincgluconate, zinc chloride and/or zinc acetate.

The composition may additionally include one of the essential ornon-essential α, L or D amino acids selected from the group consistingof lysine, arginine, histidine, phenylalanine, threonine, leucine,isoluceine, cysteine, methionine, valine, alanine, glycine, proline,glutamine, serine, tryptophan, tyrosine and asparagine.

The composition can be formulated using techniques known in the art forexample as described in Remington's Pharmaceutical Sciences, EighteenthEdition, Mack Publishing Company. The composition is preferably a gel,ointment, cream, lotion, spray or the like, suitable for topicaladministration. Advantageously, the composition of the present inventionmaintains its bioavailability at a pH suitable for topicaladministration. The composition may also include pharmaceuticallyacceptable diluents or carriers including water, carbopol, glycerin andhydroxymethyl cellulose.

The composition of the invention may additionally include excipientsknown in the art including fillers such as saccharides, for example,lactose or sucrose, mannitol or sorbitol cellulose preparations and/orcalcium phosphates, for example, tricalcium phosphate or calciumhydrogen phosphate, as well as binders such as starch paste, using forexample, maize starch, wheat starch, rice starch, potato starch,gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose,sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. In somecases, it may be desirable to add disintegrating agents such as theabove mentioned starches and also carboxymethyl-starch, cross-linkedpolyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such assodium alginate. Auxiliaries are, above all, flow-regulating agents andlubricants, for example, silica, talc, steric acid or salts thereof,such as magnesium stearate or calcium stearate, and/or polyethyleneglycol.

The compositions of the invention may contain, as additives,preservatives such as p-hydrobenzoates (nipa esters, methylparaben),sorbic acid, chlorhexidine digluconate, benzalkonium chloride andhexadecyltrimethyl ammonium bromide.

In order to accelerate the absorption of the composition through theskin, permeation accelerators such as dimethylsulfoxide orttauroglycolic acid may be added to the composition.

Hydrogel forming agents which may be used include gelatine and cellulosederivatives such as methyulcellulose, hydroxypropylcellulose andhydroxyethylcellose, as well as synthetic polymers such as polyvinylalcohol. The nature and quantity of the hydrogel forming agents used orthe mixtures thereof will depend on the particular viscosity required.

The additives which may be present also include moisture-retainingsubstances such as glycerol, sorbitol, 1,2-propyleneglycol,butyleneglycol and polyols.

USES OF THE COMPOSITIONS

The inventor has demonstrated that the improved composition of theinvention is effective in treating epidermal irritations and infectionsand their symptoms. Accordingly, the present invention also provides amethod of treating an epidermal irritation or infection comprisingadministering an effective amount of a composition comprising stannousfluoride and at least one zinc containing compound to an animal in needthereof. The zinc containing compound is preferably zinc gluconate andmay optionally include zinc chloride.

The term “effective amount” means providing an amount at dosages and forperiods of time that is effective to achieve the desired result. Thefrequency of application of the composition of the invention may rangeanywhere from one to six times a day, or as needed for the healingprocess. The course of the therapy typically ranges from one to sixtimes a day, for several days, and may be continued as long as requiredfor complete relief.

The term “animal” as used herein includes all members of the animalkingdom. Preferably, the animal is a mammal such as a human, horse, dogor cat.

The term “epidermal irritation” means any condition that adverselyaffects or irritates the skin or coat of an animal including, but notlimited to, insect bites, fleas, burns, psoriasis, dermatitis, acne andepidermal infections such as subcutaneous mycoses (sporotrichosis,phycomycosis, phacohypomycosis); Cutaneous Habronemiasis; CutaneousOnchocerciasis (Onchocerca cervicalis); Seborrhea; Dermatophilosis(Dermatophilus congolensis); Dermatophytosis (Trichophyton equinum,Trichophyton mentagrophytes, Trichophyton verrucosum); Warble fly larvae(Hypoderma spp); or Bot fly larvae (Gasterophilus nasalis/Gasterophilushemorradalis).

The term “infection” means any infection including, but not limited to,viral, bacterial, fungal and parasitic infections, that affects animals.

The viral infections that may be treated using the composition of theinvention include herpes viruses such as Herpes Simplex I which causescold sores and Herpes Zoster which causes shingles; Epstein-Barr virus;Papilloma virus which causes warts; cytomegalovirus; hepatitis virus;varicella-zoster virus which causes chicken pox; cold and flu viruses;human and feline leukemia viruses; human immunodeficiency viruses (HIVs)and viruses that cause ringworm.

The bacterial infections that may be treated using the composition ofthe invention include Streptococcus, Staphlococcus and Dermatophilusskin infections as well as mycoplasmas related to chronic sinusinfections.

The fungal infections that may be treated using the composition of theinvention include yeast infections of the oral cavity and vagina; fungalinfections of the fingernails and feed (athletes foot); and fungalinfections of the horse and cow epidermis including infections caused bythe genera Microsporum and Trichophyton.

The composition of the invention is particularly well suited for thetreatment of epidermal infections such as infections of the skin as wellas ocular or eye infections. The inventor has shown that the compositionis effective in treating many infections in human patients as well as inother mammals including horses, cats and dogs.

The present invention also provides a use of a composition comprisingstannous fluoride and at least one zinc containing compound to treat anepidermal irritation or infection. The invention further provides a useof a composition comprising stannous fluoride and at least one zinccontaining compound to prepare a medicament to treat an epidermalirritation or infection.

The following non-limiting examples are illustrative of the presentinvention:

EXAMPLES Example 1

A composition of the present invention comprising stannous fluoride(0.2%) and zinc gluconate (1.5%) was compared to a compositioncontaining stannous fluoride (0.4%) on the ability to treat cold sorescaused by herpes virus. A placebo containing glycerin only was alsoprepared. Each composition was tested on 10 patients. The results, shownin Table 1, demonstrate that the average healing time for the groupreceiving stannous fluoride with zinc gluconate was 4.2 days as comparedto 5.9 days for the group receiving stannous fluoride alone. This is asignificant reduction in healing time. In addition, the compositioncontaining zinc gluconate contained one half the amount of stannousfluoride as compared to the stannous fluoride alone composition.Consequently, the composition of the present invention provides a muchmore efficacious composition as evidenced by the reduced healing timeand reduced amount of stannous fluoride required.

Example 2

Five horses infected by the bacterium, Dermatophilus congolensis(commonly known as rain scald) were cured when several applications of a0.2% stannous fluoride/1.5% zinc gluconate gel was applied over a periodof two weeks.

Example 3

Five horses infected by fungi of the genera Microsporum and Trichophytonreceived immediate relief and were cured of the infection in a one weekperiod when treated with a 0.2% stannous fluoride/1.5% zinc gluconategel.

Example 4

Five colts suffering from warts (papilloma virus) on the muzzle, weresuccessfully cured of the disease by applying a 0.2% stannousfluoride/1.5% zinc gluconate gel to the affected area several times aday for two weeks. There was no scarring.

Example 5

Several equines were successfully treated for pastern dermatitis (greaseheel, scratches, mud fever) the cause of a staphylococcus/streptococcus/Dermatophilus infection with topical and bandaged applications of a 0.2%stannous fluoride/1.5% zinc gluconate gel.

Example 6

Several cats were treated to control ringworm and oral facial sores ofviral etiology with a 0.2% stannous fluoride/1.5% zinc gluconate gel.

Example 7

Several dogs with bacterial skin infections the result of intensescratching due to insect bites were successfully treated with severalapplications of a 0.2% stannous fluoride/1.5% zinc gluconate gel.

Example 8

A patient, burned with candle wax flame resulting in a six inch diameterburn area, used two applications of a 0.2% stannous fluoride/1.5% zincgluconate gel daily. As a result, the patient did not require the use ofpain medication and antibiotics for infection. The composition not onlyrelieved severe pain but also prevented blistering and infection. Thearea was totally healed in less than three weeks with minimal scarring.

Example 9

A patient burned on an electric heating coil of a stove did not blisterafter an immediate application of a 0.2% stannous fluoride/1.5% zincgluconate gel. The patient did not scab and the area did not getinfected.

Example 10

Other skin ailments successfully treated with several applications of a0.2% stannous fluoride/1.5% zinc gluconate gel, include acne, infectedbug bites, warts, ringworm, and psoriasis. It appears that theantimicrobial effect of stannous fluoride and the immune stimulatoryproperties of zinc gluconate synergistically enhance healing due tomicrobial infections.

Example 11

Treatment of Herpes

A composition of the present invention comprising 0.2% stannousfluoride; 0.2% zinc chloride and 1.5% zinc gluconate and the remainderglycerin was compared to a 0.4% stannous fluoride in glycerincomposition in the treatment of herpes simplex virus I (cold sores). Thestudy consisted of two groups of 10 healthy adults with cold sores. Onegroup was treated with the composition containing the zinc compounds andthe second group with the stannous fluoride alone composition. Theadults treated with the composition containing the zinc compounds had amean healing time of 3.1 days while the group treated with the stannousfluoride alone had a mean healing time of 3.9 days. As a result, thegroup treated with the composition of the invention that contained onehalf the amount of stannous fluoride as the other composition, healed ata faster rate. This study illustrates that the composition of theinvention treats herpes infections with much greater efficacy than acomposition containing stannous fluoride alone.

Example 12

Treatment of Shingles

The composition of Example 11 was used to treat several patients havinga shingles outbreak. The patients reported a relief of pain and fasthealing when treated with the composition of the invention. In addition,when compared with a composition containing stannous fluoride alone, thepatients reported less burning with the composition of the invention.

Example 13

Treatment of Bacterial Infections

One patient was treated with the composition of Example 11 for impetigowhich is a streptococcus infection of the skin. The treatment wassuccessful. Another patient used a gel formulation of the presentinvention to control a resistant staphococcus skin infection.

Example 14

Treatment of Cold and Flu

The composition of Example 11 was used to successfully treat sorethroats associated with colds and flu.

Example 15

Treatment of Mycoplasma Infection

The composition of Example 11 was used to successfully treat mycoplasmasrelated to a chronic sinus infection.

Example 16

Treatment of Fungal Infections

Fungal infections associated with human fingernails and feet (athlete'sfoot), and horse and cow epidermis as well as fungal infections of theoral cavity and vagina were successfully treated with the composition ofExample 11.

Example 17

Treatment of Cat Oral Ulcers

Cat oral ulcers of viral and rickettsial origin resulted in fast healingwhen the composition of Example 11 was applied several times.

Example 18

Treatment of Horses

The composition of Example 11 has been used to treat many show horsesfor ringworm, papilloma virus, warts on the nose and parasiticirritations including mites and fly bites. All treatments weresuccessful.

Example 19

Treatment of Bovines

The composition of Example 11 has been used to treat bovine skinconditions.

Example 20

Preparation of the Compositions of the Invention

To prepare the compositions of the invention all pharmaceutical mediumsare heated to 150° F. and percolated with nitrogen gas to displaceoxygen and eliminate water so that the stannous ion is free fromoxidation and hydrolysis during the mixing process of stannous fluoridewith zinc compounds. Suitable pharmaceutically accepted vehicles may beused separately or in combination include glycerin, water, ethanol,polyethylene glycol, polypropylene glycol, and the like. The followingprovides specific formulations that are within the scope of the presentinvention.

Component Percent by weight Stannous fluoride 0.20 Zinc gluconate 1.50Glycerin 98.30 Stannous fluoride 0.20 Zinc gluconate 2.50 Zinc chloride0.50 Glycerin 96.80 Stannous fluoride 0.20 Zinc acetate 2.50 Zincchloride 0.50 Glycerin 96.80 Stannous fluoride 0.20 Zinc gluconate 2.80Zinc chloride 0.50 L-Lysine 15.50 Glycerin 75.00 Carbopol 6.00 Stannousfluoride 0.25 Zinc gluconate 1.50 Zinc chloride 0.50 Glycerin 92.50Carbopol 3.00 Stannous fluoride 0.20 Zinc propionate 2.50 Zinc chloride0.50 Glycerin 96.80 Stannous fluoride 0.20 Zinc propionate 2.50 Zincchloride 0.50 Glycerin 97.30 Stannous fluoride 0.25 Zinc gluconate 2.25Zinc chloride 0.50 Hydroxymethyl cellulose 30.25 Glycerin 65.50 Carbopol3.25

While the present invention has been described with reference to whatare presently considered to be the preferred examples, it is to beunderstood that the invention is not limited to the disclosed examples.To the contrary, the invention is intended to cover variousmodifications and equivalent arrangements included within the spirit andscope of the appended claims.

All publications, patents and patent applications are hereinincorporated by reference in their entirety to the same extent as ifeach individual publication, patent or patent application wasspecifically and individually indicated to be incorporated by referencein its entirety.

TABLE 1 Healing Time (days) SnF2 + ZnGlu SnF2 Placebo 5 6 7 8 9 11 4 5 63 4 4 4 8 7 5 6 8 3 4 9 2 4 6 3 6 10 5 7 4 Mean = 4.2 5.9 7.2

I claim:
 1. A method of treating a fungal infection consisting of topically administering an effective amount of a composition consisting of water, stannous fluoride and zinc gluconate in an amount sufficient to prevent oxidation and hydrolysis of the stannous ion for at least three months to an animal afflicted with a fungal infection that can be treated or alleviated with stannous ion.
 2. The method according to claim 1 wherein the fungal infection is caused by Microsporum or Trichophyton.
 3. The method according to claim 1 wherein the animal is a human.
 4. The method according to claim 1 wherein the animal is a horse, cat or dog. 